Steroidal hormones are organic molecules that are synthesized in the body in an organ or gland and then carried through the blood to induce activity at a remote location. Steroidal hormones contain a perhydrocyclopentanophenanthrene moiety. Estrogens are an important class of steroidal hormones that stimulate the development and maintenance of fundamental sexual characteristics in humans. The principal naturally occurring estrogen in humans is estradiol, that plays a pivotal role in the regulation and maintenance of the androgen/estrogen balance. Estrogens have also been found useful in the treatment of certain medical conditions and diseases. For example, estradiol, a steroid hormone produced by the ovary, is useful in the treatment of osteoporosis, premenstrual syndrome, vasomotor symptoms associated with menopause, atrophic vaginitis, Kraurosis vulvae, female hypogonadism, primary ovarian failure, excessive hair growth and prostatic cancer. Estrogens are also used in combination with another female sex hormone, progesterone, to promote gonadotropin suppression and to act as an oral contraceptive.
Diethylstilbestrol, conjugated estrogens, and ethinyl estradiol have been used as steroidal estrogen substitutes for pharmaceutical administration. However, administration of steroidal hormone substitutes have been associated with a number of side effects, including myocardial infarction, thromboembolism, cerebrovascular disease, and endometrial carcinoma. In fact, while estrogens and estrogen substitutes are currently the only known effective treatment for osteoporosis, their use is severely limited due to side effects of long term steroidal treatment. Further, no new estrogen substitutes have been marketed in the last twenty years, perhaps due to certain severe side effects, including devastating birth defects, that were found associated with administration of diethylstilbestrol.
In light of problems associated with steroidal therapy, a significant amount of research has been carried out to identify effective nonsteroidal estrogen and antiestrogenic compounds. An example of a nonsteroidal antiestrogen is tamoxifen (TAM), ((Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine), which is a triphenylethylene derivative. The chemical structure of tamoxifen is illustrated in FIG. 1. Tamoxifen effectively antagonizes the growth-promoting effect of estrogens in primary target tissues such as the breast and ovum. Tamoxifen is currently marketed for treatment of breast cancer. Sales of this compound reached $200,000,000 in 1989.
In humans and in various animal species, TAM has been shown to undergo oxidative biotransformation to a number of basic or neutral oxidized metabolites. In particular, side chain alteration (N-demethylation, N,N-didemethylation and substitution of a hydroxyl group for the dimethylamino group), alone or in combination with 4-hydroxylation, has been shown to occur. 4-Hydroxy tamoxifen (4-HT) is a major metabolite. Acid metabolites of TAM, however, have not been detected.
Studies based on receptor competitive binding have shown that the basic and neutral metabolites of TAM generally possess estrogen receptor affinities and antiestrogenic activities that equal or exceed those of TAM itself. In addition, studies have demonstrated that these metabolites localize with TAM in tumors of patients on TAM therapy.
Clomiphene (2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethylethanamine) is a pharmaceutical compound closely structurally related to tamoxifen. The preparation of clomiphene is described in U.S. Pat. No. 2,914,563. Clomiphene is a nonsteroidal antiestrogen that is prescribed to induce ovulation in infertile women with physiological indications of normal estrogen levels. In the hypothalamus, clomiphene antagonizes estradiol-mediated feedback inhibition of gonadotrophin-releasing hormone secretion. Tamoxifen has also been administered to initiate ovulation in anovulatory women, and is favored therapeutically over clomiphene for this purpose because it has a lower incidence of side effects.
U.S. Pat. No. 4,894,373 to Young describes the use of clomiphene, tamoxifen, nafoxidene, and other antiestrogenic compounds in the treatment of menopause and osteoporosis.
Toremifene (2-[4-(2-chloromethyl-1,2-diphenylethenyl)phenoxy]-N,N-diethylethanamine), is a triphenylethylene compound structurally related to tamoxifen that has antineoplastic activity Hasan, Analyt. Letters 23(2), 327-334 (1990), reported that toremifene is metabolized in vivo to a number of compounds, including two metabolites in which the diethylethanamine side chain is replaced with oxyacetic acid and the methyl ester of oxyacetic acid. No biological activities have been reported for these metabolites.
While several nonsteroidal antiestrogenic compounds have been developed, very few nonsteroidal estrogenic compounds have been identified. There is strong need for nonsteroidal estrogenic compounds for use in estrogen replacement therapy, and specifically menopause therapy. It has been estimated that one-fourth of all women seek medical advice or treatment for this condition. Nonsteroidal estrogenic compounds are also needed for osteoporosis therapy, in the prevention of uterine bleeding, failure of ovarian development at the age of puberty, prevention of excessive growth of body hair, and for oral contraceptives.
Therefore, it is an object of the present invention to provide nonsteroidal compounds with estrogenic activity.